Function And Regulation Of CEACAM6 Upregulated By Snail1 In TGFβ1-mediated Colorectal Cancer Metastasis

Background: The progress of colorectal cancer(CRC) is a multistep process involved in multigene. The mortality of CRC remained high every year, one of the reasons is metastasis involved in lymph node and distant organs. Tumor metastasis is a complex process requiring multiple steps. Increasing data show that elevated TGFβ1 expression in tumor microenvironment is turning out to be a hallmark of tumor metastasis. However, the underlying molecular mechanisms of TGFβ1-dependent metastasis are poorly recognized. CEACAM6 was found to facilitate tumor metastasis by promoting EMT and the resistance of anoikis, thus we investigated whether CEACAM6 is involved in the TGFβ1-dependent tumor metastasis.Methods: First, we stimulated CRC cells HCT116 and DLD1 and CEACAM6 KD cells HCT116-shCEACAM6 and DLD1-shCEACAM6 with TGFβ1(20 ng/μl) for 24 h, then we detected the migration ability with transwell assay and EMT process with Western blot of CRC cells. Next, we constructed Snail1 KD cells HCT116 and DLD1, which then were stimulated by TGFβ1(20 ng/μl) for 24 h to detect the RNA and protein expression of CEACAM6. Besides, we inhibited the activation of AKT pathway with MK2206 before TGFβ1(20 ng/μl) stimulation to detect the role of AKT in TGFβ1-mediated increase of Snail1/CEACAM6 and migration of EMT process. Lastly, we detected the expression of Snail1 and CEACAM6 in 101 human CRC tissues to verify the role of Snail1 and CEACAM6 in promoting tumor progress.Results:Our research demonstrated that TGFβ1 could promote CRC metastasis in a CEACAM6-dependent manner. TGFβ1 was able to induce Snail1 and CEACAM6 expression, once Snail1 was KD, the increase of CEACAM6 induced by TGFβ1 was inhibited. Moreover, we demonstrated that TGFβ1 could upregulate Snail1 and CEACAM6 expression via AKT pathway thereby accelerating the migration and EMT of CRC cells. Interestingly, we found that Snail1 and CEACAM6 are expressed in human CRC tissues and associated with clinicopathologic features and CEACAM6 expression is correlated with Snail1 expression in human CRC tissues.Conclusion: In the present study, we firstly demonstrated that TGFβ1 could upregulate Snail1 and CEACAM6 expression via AKT pathway thereby accelerating the migration and EMT of CRC cells. And Snail1 and CEACAM6 are expressed in human CRC tissues and associated with clinicopathologic features and lymph node metastasis. Therefore our research provided a novel preventive and therapeutic target for CRC metastasis.